We have previously demonstrated that human lymphoid leukemias and lymphomas are monoclonal neoplasms which, although arrested during development, retain a finite capacity to differentiate when appropriately activated. These investigations allowed us to uncover the natural clonal evolution of follicular lymphoma in vivo by the use of anit-idiotype antibody. We are now examining the frequency of occurence and mechanism of tumor clonal evolution in human lymphoid neoplasms. Multiple samples from 30 patients were surveyed for clonal fidelity by Southern blot analysis of rearranged immunoglobulin or T-cell receptor genes. Evidence for a single progenitor cell was established in each case studied since at least one gene rearrangement was held in common by independent samples from each invidual. In most cases, all rearranged loci were retained in the same pattern throughout the course of disease. By contrast, we discovered a remarkably high frequency (35%) of clonal evolution among follicular B-cell lymphomas. Mechanisms of clonal evolution may include new variable region gene rearrangements, heavy chain constant region isotype switching and altered (mutated?) idiotype. Deduced genealogies of the related clones argue for an immature follicular lymphoma progenitro cell in which some immunoglobulin genes still remain in a germline configuration. Our finding of conversation of the immunoglobulin allele involved in a t(14;18) translocation, despite new rearrangements of the opposite productive allele, implicates chromosomal rearrangement as an early event in progenitor cell development.